The NF-KB signaling pathway represents an attractive therapeutic target for chronic inflammation as it regulates many gene products that control the inflammatory response. However, generalized suppression of this pathway can result in serious host toxicity, as NF-KB is a major mediator of both innate and adaptive immunity. We have formulated, characterized, and evaluated a novel peptide-siRNA construct that is self-condensing, stable in serum, and delivers oligonucleotides to the cell cytoplasm with an intrinsic endosomal releasing mechanism based on a modified version of the amphipathic cationic peptide melittin, a component of bee venom that normally forms pores in membrane by oligomerization. We showed that the modified melittin could be conjugated to myriad cargos and transport materials rapidly into the cell cytoplasm for efficient gene silencing: The peptide-siRNA complexes targeting the NF-KB p65 canonical subunit homed to the inflamed paws through leaky vasculature and potently suppressed ongoing inflammation in a murine model of RA. Extensive in vivo and ex vivo studies also suggest that the platform has a favorable toxicity profile and did not elicit immunogenicity after repeated dosing. In this proposal we will use the peptide-siRNA platform to explore the hypothesis that a dual approach (targeting both NF-KB canonical and non-canonical pathways) will have synergistic or additive benefits in the treatment of RA. To that end we will formulate and optimize peptide- siRNA constructs containing NF-KB-p65 (canonical), p52/100 (non-canonical), or a combination of both and test their efficiency for NF-KB signaling pathway knockdown in vitro in human/murine cell lines and in vivo in two murine models of inflammatory arthritis. The results will provide in vivo proof-of-concept for this new peptide- siRNA platform and the success will justify further development of this system for other disease processes that are amenable to RNA interference therapy.